Formulation of pharmaceutical dosage forms is frequently hampered by the poor aqueous solubility and stability of the drugs, which in turn can severely limit their therapeutic application. Also, the slow dissolution of solid state drug formulations and the side-effects of some drugs result from their poor aqueous solubility. Drug degradation products, formed in the pharmaceutical dosage forms, can also result in severe side-effects. Increasing drug solubility and stability through appropriate formulation can, thus, lead to increased therapeutic efficiency of the drug. Various methods have been used to increase the solubility and stability of drugs, such as the use of organic solvents, emulsions, liposomes and micelles, adjustments of pH and the dielectric constant of the solvent system, chemical modifications, and complexation of the drugs with appropriate complexing agents, e.g. cyclodextrins.
Cyclodextrins were first isolated by Villiers in 1891 as a digest of Bacillus amylobacter on potato starch [see A. Villiers: Sur la fermentation de la fecule par l'action du ferment butyrique. C.R. Acad. Sci., 112, 536-538 (1891)], but the foundations of cyclodextrin chemistry were laid down by Schardinger in the period 1903-1911 [see, for example, F. Schardinger: Uber thermophile Bacterien aus verschiedenen Speisen and Milch, sowie uber einige Umsetzungsproducte darselben in kohlenhydrathaltigen Nahrlosungen, darunter krystallisierte Polysaccharide (Dextrine) aus Starke, Z. Unters. Nahr. GenuBm., 6, 865-880 (1903)] and much of the older literature refers to cyclodextrins as Schardinger's dextrins. Until 1970, only small amounts of cyclodextrins could be produced in the laboratory and the high production cost prevented the usage of cyclodextrins in industry. In recent years, dramatic improvements in cyclodextrin production and purification have been achieved and the cyclodextrins have become much cheaper. This has made industrial application of cyclodextrins possible.
Cyclodextrins are cyclic oligosaccharides with hydroxyl groups on the outer surface and a void cavity in the center. Their outer surface is hydrophilic, and therefore they are usually soluble in water, but the cavity has a lipophilic character. The most common cyclodextrins are .alpha.-cyclodextrin, .beta.-cyclodextrin and .gamma.-cyclodextrin, consisting of 6, 7 and 8 .alpha.-1,4-linked glucose units, respectively. The number of these units determines the size of the cavity.
Cyclodextrins are capable of forming inclusion complexes with a wide variety of hydrophobic molecules by taking up a whole molecule, or some part of it, into the cavity. The stability of the complex formed depends on how well the guest molecule fits into the cyclodextrin cavity. Common cyclodextrin derivatives are formed by alkylation (e.g. methyl- and ethyl-.beta.-cyclodextrin) or hydroxyalkylation of the hydroxyl groups (e.g. hydroxypropyl- and hydroxyethyl-derivatives of .alpha.-, .beta.-, and .gamma.-cyclodextrin) or by substituting the primary hydroxyl groups with saccharides (e.g. glucosyl- and maltosyl-.beta.-cyclodextrin). Hydroxypropyl-.beta.-cyclodextrin and its preparation by propylene oxide addition to .beta.-cyclodextrin, and hydroxyethyl.beta.-cyclodextrin and its preparation by ethylene oxide addition to .beta.-cyclodextrin, were described in a patent of Gramera et al. (U.S. Pat. No. 3,459,731, issued Aug. 1969) over 20 years ago. For a comprehensive review of cyclodextrins see Cyclodextrins and their industrial uses, editor Dominique Duchene, Editions Sante, Paris, 1987. For a more recent overview, see J. Szejtli: Cyclodextrins in drug formulations: Part 1, Pharm. Techn. Int. 3(2), 15-22 (1991); and J. Szejtli: Cyclodextrins in drug formulations: Part II, Pharm. Techn. Int. 3(3), 16-24 (1991).
Numerous reports have been published with respect to the solubilizing effects of cyclodextrins. The general procedure described in these reports for preparing aqueous cyclodextrin solutions containing various drugs is as follows: An excess amount of the drug is added to an aqueous cyclodextrin solution and the suspension formed is agitated for up to one week at room temperature. Then the suspension is filtered or centrifuged to form a clear drug-cyclodextrin complex solution. For the preparation of solid formulations of the drug-cyclodextrin complex, the water is removed from the aqueous drug-cyclodextrin complex solution by evaporation in a rotation evaporator, in a spray dryer or by lyophilization. Pitha (Josef Pitha: Administration of sex hormones in the form of hydrophilic cyclodextrin derivatives, U.S. Pat. No. 4,596,795, issued Jun. 24, 1986) describes inclusion complexes of sex hormones, particularly testosterone, progesterone, and estradiol, with specific cyclodextrins, preferably hydroxypropyl-.beta.-cyclodextrin and poly-.beta.-cyclodextrin. The complexes enable the sex hormones to be successfully delivered to the systemic circulation via the sublingual or buccal route. In another patent (Josef Pitha: Pharmaceutical preparations containing cyclodextrin derivatives, U.S. Pat. No. 4,727,064, issued Feb. 23, 1988) Pitha describes formulations of a number of drugs with various cyclodextrin derivatives, mainly hydroxypropyl-.beta.-cyclodextrin but also hydroxypropyl-.gamma.-cyclodextrin. In a series of patents (N.S. Bodor: Improvements in redox systems for brain-targeted drug delivery, U.S. Pat. No. 5,002,935, issued Mar. 26, 1991; N.S. Bodor: Pharmaceutical formulations for parenteral use, U.S. Pat. No. 4,983,586, issued Jan. 8, 1991; N. S. Bodor: Redox systems for brain-targeted drug delivery, U.S. Pat. No. 5,017,566, issued May 21, 1991; and N. S. Bodor: Pharmaceutical formulations for parenteral use, U.S. Pat. No. 5,024,998, issued Jun. 18, 1991), Bodor describes formulations of a number of drugs with hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of .beta.- and .gamma.-cyclodextrin. Also, Brauns and Muller (U. Brauns and B. W. W. Muller: Pharmazeutische Praparate von in Wasser schwerloslichen oder instabilen Arznelstoffen und Verfahren zu Ihrer Herstellung, European Patent No.: 0 149 197 B1 dated Mar. 21, 1990) have described formulations of drugs with various .beta.-cyclodextrin derivatives, mainly hydroxypropyl-.beta.-cyclodextrin. The solubilizing and stabilizing effects of hydroxypropyl-.beta.-cyclodextrin on drugs have been reviewed by T. Loftsson, M. E. Brewster, H. Derendorf and N. Bodor: 2-Hydroxypropyl-.beta.-cyclodextrin: Properties and usage in pharmaceutical formulations. Pharm. Ztg. Wiss. 4/136: 5-10 (1991).
Methods of preparing drug-cyclodextrin complexes have been described by Hirayama and Uekama [F. Hirayama and K. Uekama: Methods of investigating and preparing inclusion compounds. In: D. Ducheene (editor), Cyclodextrins and their industrial uses. Editions de Sante, Paris, 1987, pp. 133-172]. In solution, the drug-cyclodextrin complexes are prepared by the simple method described above and the complexation evaluated by determination of stability constants by a solubility method, a kinetic method, a spectroscopic method or some other analytical method. On a laboratory scale, solid drug-cyclodextrin complexes are usually formed by lyophilization of drug-cyclodextrin complex solution, but on an industrial scale, other methods are also used such as the kneading method, spray-drying, coprecipitation, neutralization and grinding methods. In none of these methods are water-soluble pharmaceutical polymers, or other polymers in general, used for enhancing the drug-cyclodextrin complexation.
There are few samples of formation of drug-cyclodextrin complexes by heating. Thus, Hassan et al., Int. J. Pharm. 58, 19-24 (1990), prepared a famotidine-.beta.-cyclodextrin complex by adding the drug to aqueous .beta.-cyclodextrin solution, heating the mixture under reflux for 1 hour and then stirring it at room temperature for 5 days. The solution which formed was concentrated by evaporation under vacuum and the precipitate which formed was filtered and dried under vacuum at 50.degree. C. In a series of articles, Nakai et al. describe how they make cyclodextrin inclusion complexes by heating ground mixtures of physical mixtures to 60.degree. to 130.degree. C. in sealed containers. See Nakai et al., Chem. Pharm. Bull. 35(11), 4609-4615 (1987); Nakai et al., Chem. Pharm. Bull. 37(4), 1055-1058 (1989); Nakai et al., Chem. Pharm. Bull. 38(3), 728-732 (1990); Nakai et al., Chem. Pharm. Bull. 38(5), 1345-1348 (1990); and Nakai et al., Chem. Pharm. Bull. 39(6), 1532-1535 (1991). Finally, Schmidt and Maier [E. Schmidt and H. G. Maier: Thermostabile Bindung von Aromastoffen an Starke. Teil 2: Bindung von Menthol durch Autoklavieren, Starch/Starke, 39(6), 203-207 (1987)] describe formation of thermostable binding of menthol to various types of starches, including .beta.-cyclodextrin, by autoclaving. In none of the above mentioned articles are starches, or other polymers, used to enhance complexation of drugs by cyclodextrins.
Due to the negative enthalpy of cyclodextrin complexation, the solubility enhancement of drugs by aqueous cyclodextrin solutions is generally larger at low temperature than at high temperature [T. Loftsson and N. Bodor: Effects of 2-hydroxypropyl-.beta.-cyclodextrin on the aqueous solubility of drugs and transdermal delivery of 17.beta.-estradiol, Acta Pharm. Nord., 1(4), 185-193 (1989)]. Also, additives such as sodium chloride, buffer salts, surfactants and organic solvents (e.g. ethanol) usually reduce the solubilizing effects of cyclodextrins.